Proposal Summary/Abstract While the 5-year survival rate of the most common cancers such as lung, colon, breast, and prostate cancer have improved over the last several decades, the 5-year survival rate of Pancreatic Ductal Adenocarcinoma (PDAC) have remained flat-lined at only 3%-7%. The aggressive nature of PDAC often subjugates the effects of current treatment options, and the lack of screening tools make early detection rare. The later stages of PDAC have been thoroughly characterized and studied, but the understanding of early pancreatic cancer development remains limited. The large body of published research supports the idea that pancreatic lesions originate from acinar cells that transdifferentiate into ductal-like cells- a process called acinar to ductal metaplasia (ADM). Broadly stated, this proposal aims to develop a better understanding of what drives ADM initiation and the role of ADM drivers in maintaining PDAC development. Our supporting in vitro data suggest that overexpression of transcriptional repressor REST in pancreatic acinar cells can sufficiently induce ADM transformation. While REST has been well characterized for its gene regulating role in neurogenesis, the functionality of REST in pancreatic cancer tissue remains largely unexplored. This proposal will use Chromatin Immunoprecipitation to identify direct binding targets of REST within pancreatic acinar cells, giving insight into the mechanism underlining the effects of REST in ADM progression. To determine if REST activity is necessary for ADM progression and PDAC development in vivo, this proposal will develop a novel REST mouse model with conditional knock-out of REST expression within acinar pancreatic cells. The effects of conditional REST knockout on ADM and early pre-cancerous lesions will be determined by inducing pancreatitis (PDAC pre- disposing factor) and quantifying ADM transformation. Furthermore, we will determine the effect of conditional REST knockout on impeding PDAC development and prolonging survival by crossing REST knockout mice with an established transgenic PDAC model. Our goal is to establish the role of REST activity in early and late PDAC to ultimately offer a new therapeutic target that serves as a prevention intervention for patients at high-risk of PDAC development and treatment intervention for PDAC patients.